Abstract: Cerebral injury is a major and debilitating complication of sickle cell disease (SCD). These injuries begin early in the development of children with SCD and often progress throughout their lives. Types of cerebral injury include stroke, silent cerebral infarct (SCI), transient ischemic attacks and subclinical injury. Detection of these events can be difficult and expensive, and preventive measures are limited. There is a critical need for clinical laboratory tests for early detection of injury in the developing brains of patients with SCD to monitor progression and treatment effect. A previous study conducted by our team using a single analyte immunoassay that we developed showed that glial fibrillary acidic protein (GFAP) is elevated in pediatric SCD patients vs. healthy children, detects acute infarcts and correlates negatively with IQ. Meso Scale Diagnostics (MSD) has recently created a multiplexed immunoassay panel for detection of biomarkers of traumatic brain injury (TBI) in adults. This comprehensive, highly sensitive panel measures very low levels (fg-pg/mL) of known TBI biomarkers (tau, GFAP, S100?, UCH-L1, BDNF, NSE, MMP-9, CKBB, NRGN, NPTX1, PRDX6, NF-L, MCP-1 and VILIP-1) in plasma and sera. Our primary goal for this proposal is to determine if the blood levels of one or more of these established TBI biomarkers correlate with brain injury confirmed by magnetic resonance imaging (MRI) or neurocognitive assessment in children with SCD. To test the TBI biomarker panel in children with confirmed brain injury, plasma samples from the Silent Infarct Transfusion (SIT) trial will be assayed. The SIT trial tested whether regular blood transfusions could reduce the recurrence or progression of SCI and incidence of overt stroke confirmed by MRI, as well as the decline in neurocognition that is seen with these injuries (as determined by Wechsler and BRIEF assessments), in children with SCD. In this proposal, SIT screening plasma from children with SCD that are either SCI positive (SCI+) or negative (SCI-), as adjudicated by MRI at trial entry, will be assayed for the brain injury biomarkers that correlate with TBI in adults, to determine if they can differentiate the SCI+ group from the SCI- group and healthy controls. Plasma from time points 0, 6, 12, 24 and 36 months from SCI- and SCI+ participants (randomized to transfusion or observation) will be assayed to study temporal patterns of the brain injury biomarkers over a 3-year period. We will also assess the effect of treatment assignment (transfusion vs. observation) and look for correlations with new neurologic injuries and events that occurred during the study, including exit MRI. Using linear regression modeling, correlations between the levels of the biomarkers and neurocognitive assessments will be explored to identify biomarkers of neurocognitive decline in children with SCD. This study will leverage important existing resources to find biomarkers that measure brain injury and subtle changes in cognition, which could reduce or obviate the need for expensive tests such as MRI, provide important clues to the etiology of brain injury in SCD, and serve as much needed clinical laboratory tools for children and adults with SCD and other brain injury disorders.